Potassium citrate is used clinically to treat kidney stones by alkalizing the urinary pH and increasing urinary citrate concentration. However, its therapeutic efficacy is limited by its gastrointestinal complications such as irritation and ulcerations. Extended-release tablets of potassium citrate could minimize these side effects and have been shown to lead to sustained elevation of urinary pH and citrate concentration (Pak et al., 1984).
Considerable difficulties have been encountered in the preparation of extended-release matrix tablets containing potassium citrate. Potassium citrate is very soluble in water and the dosage required is very high. The only way to extend the release of potassium citrate tablet while keeping the tablet size acceptable for swallowing is to use a hydrophobic wax matrix, such as carnauba wax, wherein the total amount of inactive ingredients is below 25% w/w.
When the drug content is low, the carnauba wax can be dry mixed with the drug and other inactive ingredients prior to compression. For example, U.S. Pat. No. 4,904,478 teaches an extended-release wax matrix tablet of a highly water-soluble drug, sodium fluoride, wherein the carnauba wax, present at 35-70% w/w of the tablet weight, is dry mixed with the drug and other inactive ingredients prior to compression.
In the case of potassium citrate, because the drug dosage is high, the inactive ingredients including the extended-release agent(s) must be kept below 25% w/w to keep the tablet size acceptable for swallowing. If carnauba wax is used at less than 25% w/w, prior art teaches that the drug and carnauba wax should be heated until the carnauba wax liquefies, as described in Example 1 of US 2008/0131504 A1 (Mission Pharmacal, San Antonio, Tex., USA) to give an acceptable extended-release profile and friability. Friability is a measure of the durability of the tablet from the time it is compressed, to packaging, and to the time of use.
The process of US 2008/0131504A1 for making extended-release potassium citrate tablet containing carnauba wax is difficult. Heating until the carnauba wax liquefies requires a lot of time and then there is the problem of discharging the molten potassium citrate-carnauba wax mixture from the mixer. The cooled mass is extremely hard; therefore the molten mass must be poured into molds so that the cooled mixture is of appropriate size for feeding into a comminuting machine.
A simpler process for making the extended-release potassium citrate tablet is described in PCT/PH2012/000013, which surprisingly found that extended-release potassium citrate tablets containing carnauba wax could be produced without melting the wax. The potassium citrate-carnauba wax mixture is heated to a temperature below the temperature at which carnauba wax liquefies, and then discharged from the mixer as granules. The temperature is preferably higher than 55° C., and most preferably higher than 60° C. The cooled granulate can then be fed directly into a comminuting machine for size reduction, after which a lubricant is added, and the final mixture compressed into tablets. The tablet produced according to PCT/PH2012/000013 has the same dissolution profile as tablet produced by totally melting the wax. Hereafter, we will use melt-granulation and heat-granulation to refer to the processes described in US 2008/0131504A1 and PCT/PH2012/000013, respectively.
Mission Pharmacal, the innovator of the extended-release potassium citrate tablet, sells the tablet under the brand name Urocit-K, in three strengths: 5-meq, 10-meq, and 15-meq tablets. The daily dose of Urocit-K is 30-60 meq, which requires 6-12 tablets of the 5-meq, 3-6 tablets of the 10-meq, and 2-4 tablets of the 15-meq. Urocit-K is a wax matrix tablet containing potassium citrate, carnauba wax as extended-release agent, and magnesium stearate as lubricant.
Because of the large daily dose of potassium citrate, the preferred strength is the high dose 15-meq tablet. However, the 15-meq Urocit-K tablet, the only high dose tablet commercially available, has difficulty complying with the USP dissolution requirement. There is therefore a need for a robust high dose extended-release potassium citrate tablet that consistently passes USP dissolution requirement and with acceptable friability.